Sirtuins are NAD-dependent deacetylases that have been implicated in aging and metabolism in organisms ranging from bacteria to mice. In mammals, there are seven sirtuins termed SIRT1-7. Three (SIRT1, 6, and 7) are primarily nuclear, three (SIRT3-5) are mitochondrial and SIRT2 is cytoplasmic. Numerous studies show that mammalian sirtuins mediate effects of diet on protein acetylation, metabolism and aging. At least some of the health-promoting effects of calorie restriction (CR) can be elicited by raising levels of SIRT1 in mice. These include protection against metabolic decline caused by high fat diets or normal aging, and protection against neurodegenerative diseases in mice engineered to model, for example, Alzheimer's disease. Thus a general picture arises that SIRT1 activity increases in CR to help mediate protection against diseases of aging. Our own unpublished findings show that when SIRT1 is deleted from pituitary, the major hormonal axes driving growth and reproduction are reduced, like in dwarf mice. Since these changes are induced by CR in wild type mice, this phenotype suggests that unlike in peripheral tissues, SIRT1 activity in pituitary is repressed by CR, which we confirmed. This remarkable finding expands the role of pituitary SIRT1 in pituitary to promoting growth and reproduction when food is abundant (in addition to its role in promoting protection is other tissues when food is scarce). Aim 1 of this proposal will flesh out the mechanism by which SIRT1 mediates its effects in the pituitary. It will also probe how pituitary SIRT1 is regulated by diet. This aim may also provide insight into why whole-body activation of SIRT1 slows aging but does not extend life span. Finally, it will probe whether increasing levels of SIRT1 in the pituitary extends the reproductive life span of mice. The central role of SIRT1 in driving reproduction begs the question whether this sirtuin also controls gametogenesis in a cell autonomous manner. Preliminary findings say it does. Aims 2 and 3 will delete or over-express SIRT1 in testes (Aim 2) or oocytes (Aim 3) and determine consequences on gametogenesis, reproductive life span, and the quality of progeny produced. These findings may identify new mechanisms to slow aging in germ cells, and lead to new practical strategies for infertility in humans. PUBLIC HEALTH RELEVANCE: Sirtuins are NAD-dependent deacetylases that slow aging in model organisms and mammalian tissues, such as muscle and bone. Our new findings suggest that the mammalian sirtuin SIRT1 also drives growth and reproduction via the pituitary. This new project will probe the central function of pituitary SIRT1 in hormonal control and also the cell---autonomous functions of SIRT1 in the male and female gametes.